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US009856497B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 ,856 ,497 B2 Qi et al. (45 ) Date of Patent: Jan . 2 , 2018 ( 54 ) CHIMERIC PROTEINS AND METHODS OF 9 , 593 , 338 B2 3 / 2017 Liu et al . REGULATING GENE EXPRESSION 9 ,624 ,554 B2 4 /2017 Collins et al . 2004 /0197346 Al 10 / 2004 O 'Hare et al. 2006 /0182741 A1 8 / 2006 Bourel et al. @( 71 ) Applicant: THE BOARD OF TRUSTEES OF 2007 /0224615 Al 9 /2007 Lee et al. THE LELAND STANFORD JUNIOR 2007 /0231319 A1 10 /2007 Yednock et al. UNIVERSITY , Stanford , CA (US ) 2008 /0274913 AL 11 / 2008 Lee 2010 / 0076057 A1 3 / 2010 Sontheimer et al. 2010 / 0093617 AL 4 / 2010 Barrangou et al. @( 72 ) Inventors : Lei S . Qi, Stanford , CA (US ) ; P . C . 2011 / 0217739 AL 9 / 2011 Terns et al . Dave P . Dingal, Stanford , CA (US ) 2012 / 0077706 A1 * 3 / 2012 Lee . .. .. .. .. C12N 15 / 1055 506 / 11 @( 73 ) Assignee : The Board of Trustee of the Leland 2013 /0011828 A1 1 / 2013 Barrangou et al. Stanford Junior University , Stanford , 2014 / 0068797 Al 3 / 2014 Doudna et al. CA (US ) 2014 /0113376 Al 4 /2014 Sorek et al. 2014 /0179770 A1 * 6 /2014 * ZhangLilang . C12N 15 / 86 @ 514 /44 R ( * ) Notice: Subject to any disclaimer, the term of this 2014 /0199767 Al 7 / 2014 Barrangou et al . patent is extended or adjusted under 35 2014 /0234851 A1 8 / 2014 Leonard et al. U . S . C . 154 (b ) by 0 days . 2014 /0271635 Al 9 /2014 Brogdon et al . 2014 /0273226 AL 9 /2014 Wu ( 21 ) Appl. No .: 15 /403 , 058 2014 / 0294773 A1 10 / 2014 Brouns et al. 2014 /0295556 Al 10 /2014 Joung et al. 2014 / 0295557 A1 10 /2014 Joung et al . (22 ) Filed : Jan . 10 , 2017 2014 / 0315985 A 10 / 2014 May et al . 2014 /0342456 AL 11 /2014 Mali et al . (65 ) Prior Publication Data 2014 /0342457 AL 11/ 2014 Mali et al . 2014 /0342458 A1 11 /2014 Mali et al . US 2017 /0198308 A1 Jul. 13, 2017 (Continued ) Related U . S . Application Data FOREIGN PATENT DOCUMENTS ( 60 ) Provisional application No . 62/ 277 , 322 , filed on Jan . 11 , 2016 , provisional application No . 62 /351 ,522 , CA 2619833 Al 3 / 2007 filed on Jun . 17 , 2016 , provisional application No . EP 1916903 B1 7 /2010 62 /399 ,902 , filed on Sep . 26 , 2016 . (Continued ) (51 ) Int. CI. OTHER PUBLICATIONS CO7H 21/ 04 (2006 .01 ) ( 2006 .01 ) Cheng et al ( Cell Research , 2013 , 23 : 1163 - 1171 ). * C12N 15 / 90 Chavez et al (Nature Methods, 2015 , 12 : 326 - 310 ). * C12N 9 / 22 ( 2006 .01 ) Nunez et al ( ACS Chem . Biol .; Feb . 9 , 2016 ; 11: 681 -688 ). * ( 52 ) U .S . CI. Invitrogen “ TangoTM GPR21 - bla U2OS Cell -based Assay , " printed CPC .. .. C12N 15 / 907 (2013 .01 ) ; C12N 9 /22 2010 , p . 1 - 12 . ( 2013 .01 ) ; C12Y 301/ 00 (2013 .01 ) Lim et al (Nature Reviews, 2010 , 11 : 393 -403 ) * ( 58 ) Field of Classification Search Daringer et al (ACS Synthetic Biology , 2014 , 3 :892 - 902 ) .* None Wehr et al ( Chapter 8 ; G protein - Coupled Receptor Screening See application file for complete search history . Assays , Methods in Molecular Biology , Jan . 2015 ; vol. 1272 , p . 107 - 118 ). * (56 ) References Cited Qi et al ( Cell, 2013, 152 : 1173 - 1183 ) .* U . S . PATENT DOCUMENTS (Continued ) 5 , 888 , 813 A 3 / 1999 Endl et al. 7 , 049 , 076 B2 . 5 / 2006 Lee et al . Primary Examiner — Laura B Goddard 8 , 017 , 398 B2 9 / 2011 Lee et al. 8 , 546 , 553 B2 10 / 2013 Terns et al . (74 ) Attorney , Agent, or Firm — Kilpatrick Townsend & 8 , 697, 359 B1 4 / 2014 Zhang Stockton LLP 8 ,771 , 945 B1 . 7 / 2014 Zhang 8 , 795 , 965 B2 8 / 2014 Zhang 8 , 865 ,406 B2 10 / 2014 Zhang et al. (57 ) ABSTRACT 8 ,871 ,445 B2 10 / 2014 Le Cong et al . 8 , 889 , 356 B2 11/ 2014 Zhang The present disclosure provides systems, compositions and 8 , 895 ,308 B1 11/ 2014 Zhang et al. 8 , 906 , 616 B2 12 / 2014 Zhang et al. methods for regulating expression of a target polynucleotide 8 , 932 , 814 B2 1 /2015 Le Cong et al. in a cell. The systems, compositions and methods comprise 8 , 945, 839 B2 2 / 2015 Zhang a chimeric receptor polypeptide comprising a G -protein 8 , 993 , 233 B2 3 / 2015 Zhang et al. 8 , 999 , 641 B2 4 / 2015 Zhang et al. coupled receptor (GPCR ) or a fragment thereof, a chimeric 9 , 023 , 649 B2 5 / 2015 Mali et al . adaptor polypeptide, at least one actuator moiety and a 9 , 234 , 213 B2 1 / 2016 Wu cleavage moiety . 9 , 260 , 752 B1 2 / 2016 May et al. 9 , 580, 480 B2 2 / 2017 Lu et al. 9 , 587, 020 B2 3 /2017 Wu et al . 30 Claims, 49 Drawing Sheets US 9 ,856 ,497 B2 Page 2 References Cited WO 2015139139 9 / 2015 ( 56 ) WO 2015142661 9 /2015 U . S . 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    Journal of Cancer 2019, Vol. 10 1622 Ivyspring International Publisher Journal of Cancer 2019; 10(7): 1622-1632. doi: 10.7150/jca.27780 Review The Prospective Value of Dopamine Receptors on Bio-Behavior of Tumor Xu Wang1,2, Zhi-Bin Wang1,2, Chao Luo1,2,4, Xiao-Yuan Mao1,2, Xi Li1,2, Ji-Ye Yin1,2, Wei Zhang1,2,3, Hong-Hao Zhou1,2,3, Zhao-Qian Liu1,2,3 1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China; 2. Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China; 3. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, P. R. China; 4. School of Life Sciences, Central South University, Changsha, Hunan 410078. Corresponding author: Professor Zhao-Qian Liu: Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, P. R. China; Institute of Clinical Pharmacology, Central South University; Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, P. R. China. Tel: +86 731 89753845, Fax: +86 731 82354476, E-mail: [email protected]. © Ivyspring International Publisher. This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2018.06.10; Accepted: 2019.02.07; Published: 2019.03.03 Abstract Dopamine receptors are belong to the family of G protein-coupled receptor. There are five types of dopamine receptor (DR), including DRD1, DRD2, DRD3, DRD4, and DRD5, which are divided into two major groups: the D1-like receptors (DRD1 and DRD5), and the D2-like receptors (DRD2, DRD3, and DRD4).
  • Binding Mode Exploration of B1 Receptor Antagonists' by the Use of Molecular Dynamics and Docking Simulation—How Different T

    Binding Mode Exploration of B1 Receptor Antagonists' by the Use of Molecular Dynamics and Docking Simulation—How Different T

    International Journal of Molecular Sciences Article Binding Mode Exploration of B1 Receptor Antagonists’ by the Use of Molecular Dynamics and Docking Simulation—How Different Target Engagement Can Determine Different Biological Effects Marica Gemei 1,*, Carmine Talarico 1 , Laura Brandolini 1, Candida Manelfi 1, Lorena Za 2, Silvia Bovolenta 2, Chiara Liberati 2, Luigi Del Vecchio 3, Roberto Russo 4 , Carmen Cerchia 4, Marcello Allegretti 1 and Andrea Rosario Beccari 1 1 Dompé Farmaceutici SpA, via Campo di Pile, 67100 L’Aquila, Italy; [email protected] (C.T.); [email protected] (L.B.); candida.manelfi@dompe.com (C.M.); [email protected] (M.A.); [email protected] (A.R.B.) 2 Axxam, Via Meucci 3, Bresso, 20091 Milano, Italy; [email protected] (L.Z.); [email protected] (S.B.); [email protected] (C.L.) 3 Ceinge Biotecnologie Avanzate, via G. Salvatore 486, 80145 Napoli, Italy; [email protected] 4 Department of Pharmacy, University of Naples “Federico II”, via D. Montesano, 49, 80131 Napoli, Italy; [email protected] (R.R.); [email protected] (C.C.) * Correspondence: [email protected]; Tel.: +34-06-465916 Received: 26 August 2020; Accepted: 12 October 2020; Published: 16 October 2020 Abstract: The kinin B1 receptor plays a critical role in the chronic phase of pain and inflammation. The development of B1 antagonists peaked in recent years but almost all promising molecules failed in clinical trials. Little is known about these molecules’ mechanisms of action and additional information will be necessary to exploit the potential of the B1 receptor.